Nanoparticles are tiny particles which sizes are less than 100 nm and have many industrial applications due to their novel physical and chemical properties. Some of those applications are in the field of nanobiotechnology, drug delivery, catalysis, fluorescent biological labels, biodetection of pathogens, chemical sensors, optical/electronic/magnetic devices, and medicine.
The development of a large number of synthetic techniques has permitted the use of many different types of materials to obtain very diverse sizes of nanoparticles, from hundreds down to just a few nanometers. However, the main concern of using nanoparticles in nanomedicine is their potential toxicity for living systems mainly derived from accumulation in different tissues and organs.
It is known that the exhibited physical and chemical properties of the nanoparticles are often size-dependent. Several approaches for the synthesis of controlled-molar mass and narrow size distribution to guarantee the uniformity of the resulting nanoparticles as much as possible in a large scale have been developed. One of these approaches comprises the use of the click reaction chemistry.
A reaction process needs to comply with the following requirements to be classified as a click reaction process: to have a single-reaction trajectory; to be chemoselective; to be wide in scope (i.e., applicable under a broad range of conditions with a multitude of starting substrates); to be modular; to give stable compounds; and to show high yields. Additional requirements for reactions involving one or more polymeric reagents to be classified as click reactions are: to operate in fast time-scales; and to proceed with equimolarity.
Three different methods have been developed for single-chain nanoparticle construction via click chemistry: intrachain homocoupling, intrachain heterocoupling, and crosslinker-induced collapse. Particularly, the crosslinker-induced collapse process involves the addition of a crosslinker to generate intra-molecular crosslinking of a single polymeric chain to give discrete single-chain polymeric nanoparticles via click chemistry. The reaction comprises the linkage of the crosslinkable groups of the crosslinking agent with the complementary reactive groups of the polymer chain. The size of the resulting nanoparticles is accurately controlled by either the initial degree of polymerization of the polymeric precursor or the level of incorporation of the crosslinking agent.
Even though the efficiency of this technique has been recognized, this strategy suffers from some drawbacks. One of these drawbacks is the generation of by-products obtained by the undesired inter-molecular crosslinking reaction between different polymeric chains. To avoid these undesired inter-molecular reactions, the use of ultra-dilute reaction conditions are required. However, these conditions compromise the viability of the large scale synthesis of nanoparticles using this process and does not ensure that the inter-molecular cross-linking reactions are entirely avoided.
Additional drawbacks of the above mentioned synthetic click processes are the demanding experimental reaction conditions required. For instance, the use of organic solvents, and the use of catalysts limit their broad use at a large scale because further puryfing and refinements steps are required. Additionally, either starting materials such as polymeric precursors, crosslinking agent, and/or obtained nanoparticles can be incompatible with the experimental conditions required in the reaction.
Other processes for the preparation of single-chain polymeric nanoparticles have been disclosed in the state of the art. These processes are carried out under high temperatures. The use of high temperatures is a drawback for their industrial scale-up.
Therefore, several improvements for carrying out the above crosslinker-induced collapse reaction process under mild conditions have been disclosed in the state of the art. The reduction of the temperature and/or the removal of organic solvents and catalyst have been studied.
However, it is disclosed in the state of the art that the temperature is a critical parameter to obtain nanoparticles. Additionally, the requirements of severe anhydrous reaction medium for carrying some of the above mentioned click reactions due to the presence of water-incompatible catalysts/initiators limit the industrial production of single-chain polymeric nanoparticles.
Therefore, from what is known in the art, it is derived that there is still the need of providing a scale-up process for the preparation of water-soluble nanoparticles under mild conditions.